Gordon F. Vawter

Epstein-Barr virus-induced diseases in boys with the X-linked lymphoproliferative syndrome (XLP): Update on studies of the registry

Analyses of 100 subjects with the X-linked lymphoproliferative syndrome (XLP) in 25 kindreds revealed four major interrelated phenotypes: infectious mononucleosis, malignant B-cell lymphoma, aplastic anemia, and hypogammaglobulinemia. Eighty-one of the patients died. Two male subjects were asymptomatic but showed immunodeficiency to Epstein-Barr virus (EBV). Seventy-five subjects had the infectious mononucleosis phenotype and concurrently, 17 subjects of this group had aplastic anemia. All subjects with aplastic anemia died within a week. Aplastic anemia did not accompany hypogammaglobulinemia or malignant lymphoma phenotypes. Hypogammaglobulinemia had been detected before infectious mononucleosis in three subjects, after infectious mononucleosis in five subjects, and was not associated with infectious mononucleosis in 11 boys with hypogammaglobulinemia. In nine subjects infectious mononucleosis appeared to have evolved into malignant lymphoma; however, the majority of patients with malignant lymphoma showed no obvious antecedent infectious mononucleosis. One subject had infectious mononucleosis following recurrent malignant lymphoma. Twenty-six of 35 lymphomas were in the terminal ileum. Results of immunologic and virologic studies of 15 survivors revealed combined variable immunodeficiency and deficient antibody responses to EBV-specific antigens. Mothers of boys with XLP exhibited abnormally elevated titers of antibodies of EBV. Subjects of both sexes with phenotypes of XLP should be investigated for immunodeficiency to EBV. Persons with inherited or acquired immunodeficiency may be vulnerable to life-threatening EBV-induced diseases.

Bone sarcomas as second malignant neoplasms following childhood cancer

This study explores the relationship between histologic variants of bone sarcomas and previous therapy in patients in whom an unrelated malignant neoplasm had been diagnosed during childhood. Sarcomas of bone were the most common second malignant neoplasm (SMN) reported to the Late Effects Study Group, a 13‐institution consortium consisting of pediatric oncology centers from western Europe, Canada, and the United States. The authors attempted to relate the histologic subtypes of the 91 bone tumors to clinical factors such as previous therapy and genetic predisposition because morphologic variants have been shown to have biologic significance in other tumors and may have etiologic import. The literature concerning the subtypes of bone tumors, clinical and experimental, is also reviewed. The authors also investigated the effect of several factors on the time interval from the first diagnosis to the SMN (i.e., the bone sarcoma). Anthracyclines significantly shortened the interval by about 3 years. The primary diagnosis also significantly affected the interval, with leukemia/lymphomas having the shortest interval and retinoblastoma the longest. The authors could not demonstrate any significant relationship between morphologic characteristics of the osteosarcoma and predisposing conditions. However, lesions diagnosed as chondrosarcoma and malignant fibrous histiocytoma occurred almost exclusively in patients who had received radiation therapy to the site in which the SMN developed.

Delayed Central Nervous System Myelination in the Sudden Infant Death Syndrome

This study was designed to assess whether development of the central nervous system (CNS) is delayed in victims of the sudden infant death syndrome (SIDS). We selected the parameter of myelination because it is a continuously changing and readily accessible marker of CNS development in the SIDS age-range. We assessed myelination blindly in 61 SIDS and 89 autopsy controls. In 62 sites the degree of myelination was visually graded in myelin-stained histological sections on an ordinal scale of 0-4 using the inferior cerebellar peduncle as an internal standard of degree 3. Cases were stratified by postconceptional age at death and SIDS and controls were compared with respect to myelin degree at each site. Significantly delayed myelination (p < 0.05) occurred in the SIDS group in 25 of the 62 sites examined. Hypomyelination affected fiber systems in which myelination is initiated before or after birth and which myelinate with different tempos and preferentially affect pyramidal and cerebellar (somatomotor) and prefrontal-temporal-limbic (visceromotor) systems. Hypomyelination was not associated with individual clinicopathologic variables in the SIDS group. Somatic growth and brain weight were significantly greater in SIDS than controls. Therefore, we suggest that SIDS is associated with a developmental CNS disorder. Although delayed CNS myelination most likely shares a common antecedent with sudden death and is not its cause, the role of somato- and visceromotor systems in central cardiorespiratory control and arousal warrants further analysis in SIDS.

Pulmonary vascular disease in fatal meconium aspiration

Although not proved, it is generally accepted that pulmonary vasospasm is responsible for the persistent pulmonary hypertension frequently associated with meconium aspiration. We have studied the pulmonary vasculature in 11 consecutive infants with fatal meconium aspiration, applying morphometric techniques to pulmonaryarteries distended with barium gelatin before fixation. In 10 of the 11 infants, persistent pulmonary hypertension was evident clinically, with right-to-left shunting through the foramen ovale or ductus arteriosus. In all but one, severe structural abnormal muscularization of the smallest intra-acinar arteries was present. These changes must have developed before birth. In only one infant was the structure of the intra-acinar precapillary arteries virtually normal, as would be expected if vasospasm alone had caused the hypertension. The persistent pulmonary hypertension associated with fatal meconium aspiration may be the result of a structurally abnormal pulmonary microcirculation.

Malignant lymphoma after diphenylhydantoin (dilantin) therapy

A history of prolonged diphenylhydantoin (Dilantin) therapy was reported by 8 of 516 patients (1.6%) with Hodgkins disease or non‐Hodgkins lymphoma, as compared with 3 of 516 patients (0.6%) with other cancers, and 2 of 516 (0.4%) tumor‐free individuals. The findings, together with other published data, suggest a small excess risk of malignant lymphomas in patients receiving long‐term treatment with this drug. The immunosuppressive effects of chronic diphenylhydantoin therapy may be involved in the pathogenesis of these neoplasms.

Tumors of the exocrine pancreas in children and adolescents. A clinical and pathologic study of eight cases.

Eight patients with a tumor of the exocrine pancreas were treated or seen in consultation at the Childrens Hospital Medical Center over the last 30 years. There were five girls and three boys ranging in age from 15 months to 18 years (average age: 8 years). Tumors were surgically resectable in six of eight cases–three by modified Whipple procedure and three by local resection. The average diameter of tumor was 13.6 cm (range: 3.8–20 cm). There were three adenocarcinomas of duct cell type, two acinar cell carcinomas, two acinar cell adenomas, and a papillary-cystic tumor of low-grade malignancy. One of the adenocarcinomas arose in a field of orthovoltage radiation and another occurred in a patient with tuberous sclerosis. Five of eight patients died, four with regional or distant metastases documented at autopsy. The patient with the papillary-cystic tumor experienced several local recurrences but was alive 14 years after initial surgery. Data from the literature indicate that acinar cell tumors are proportionately more common in children than in adults and have a somewhat better prognosis than tumors of duct cell type. Further reporting of cases with long-term follow-up is encouraged in order to gain clearer perspective of nonendocrine tumors of the pancreas in childhood.

Primary bronchial tumors in childhood: A clinicopathologic study of six cases

A primary bronchial tumor was diagnosed in six children younger than age 12 years. These cases include four bronchial carcinoids, a low‐grade mucoepidermoid carcinoma, and a granular cell tumor (“myoblastoma”). Lobar or segmental resection was performed in each case and remains the treatment of choice. The most common bronchial tumors in childhood are carcinoids with 17 other evaluable cases in the English Literature. This series includes the youngest child to be reported with bilateral choroidal metastases leading to blindness; in addition, there were clinical manifestations of gigantism and acromegaly possibly related to ectopic hormone production. Low‐grade mucoepidermoid carcinomas rank second in frequency to carcinoids and have an excellent prognosis. Judging from the childhood bronchial tumors reported to date, proved examples of bronchogenic carcinoma are vanishingly rare.

Granulosa theca cell tumors in premenarchal girls: A clinical and pathologic study of ten cases

Granulosa theca cell tumor (GTCT) in the premenarche accounted for 7% of all ovarian tumors treated at the Childrens Hospital Medical Center from 1928 through 1979. The average age of the ten girls at the time of diagnosis was 5 years (range 11 months–121/2 years) with precocious “pseudopuberty” and an abdominal mass being the most common presentation. GTCTs were solitary (five right, five left) with an average diameter of 12.1 cm. Histologic examination showed a predominantly diffuse or solid pattern with prominent luteinization; Call‐Exner bodies and folded (“coffee‐bean”) nuclei were inconspicuous. Ultrastructural examination of one GTCT confirmed the presence of both granulosa and theca components with the latter showing extensive luteinization; estradiol, testosterone and prolactin were demonstrated in the same tumor using immunologic techniques. The average follow‐up time was 21 years with nine of the ten patients being followed for more than ten years. Salpingo‐oophorectomy resulted in cures despite the occurrence of tumor spillage in two patients. The prognosis for GTCTs in the premenarche appears more favorable than for those occurring in adulthood, but further study is needed to completely define their full biologic potential; the significance of subsequent breast cancer in two long‐term survivors merits further investigation as well.

Immunoperoxidase localization of human papillomavirus in laryngeal papillomas.

Five antigenically distinct serotypes of human papillomavirus (HPV) cause various cutaneous verrucae with distinct clinical features. Laryngeal and other mucosal papillomas, also suspected to have a viral etiology, were examined for the presence of a genus-specific (common) antigen of HPV using a peroxidase-antiperoxidase (PAP) technique. The primary antiserum used was reactive against laryngeal papillomas from 26 of 35 randomly selected patients (74%); overall, 49 of the 102 squamous papillomas stained were positive for HPV (48%). HPV antigen was not demonstrated within frankly dysplastic squamous cells. Nuclear localization of virus was confirmed by electron microscopy in 3 cases positive for HPV. PAP localization of HPV is rapid and more efficient than routine electron microscopy. Our data indicate a common pathogenesis for some papillomas and cutaneous verrucae and suggest a future role for immunohistochemistry in evaluating the epidemiology and pathobiology of laryngeal papillomatosis.

Favorable outlook for children with mediastinal neuroblastoma

Abstract Twenty-seven infants and children between the ages of 2 wk and 8 yr have been treated for mediastinal neuroblastoma, and 23 are alive, 20 more than 2 yr. Fourteen patients were under 1 yr of age, and eight were over 3 yr at diagnosis. Tumor was limited to the mediastinum in 11 children but had metastasized in 16 children to cervical nodes (10), bones (5), and epidural space (3). The primary tumor was completely excised in eight and incompletely in 16. The mass was not removed in three patients. Radiotherapy (1000–4200 R) was administered to 25 patients. Chemotherapy, usually with nitrogen mustard and long-term cyclophosphamide, was employed in 23. The four deaths occurred in children over 212 yr of age, all of whom had widespread tumor in bones at diagnosis, and in three the primary tumor was never excised. A large primary tumor, lymph node or epidural metastases, Horners syndrome, erosion of ribs and thoracic vertebrae, and incomplete surgical excision did not adversely affect the prognosis.